Basically, lactation is regulated by a dynamic balance between endocrine stimulation and feedback inhibition from local “milk stasis” signals (Wilde, C. J., Knight, C. H. & Flint, D. J. Control of milk secretion and apoptosis during mammary involution. J. Mammary Gland Biol Neoplasia 4, 129-136. (1999)). Milk stasis feedback may contribute to lactational insufficiency in women, and is an important limiting factor in the production of milk in dairy animals. Various serotonin receptor genes are expressed in mammary cells, and therefore the components of an autocrine/paracrine serotonin network are present in the mammary gland. The present invention provides for a method that disrupts serotonin synthesis and signaling causing elevated milk protein gene expression and milk yield. Therefore, the present invention provides for methods for manipulating milk production in women, and in non-human animals.
Serotonin, or 3-(β-aminoethyl)-5-hydroxyindole (5-hydroxytryptophan, or “5-HT”) is a neurotransmitter in the central nervous system which is known to play an important role in the pathogenesis of affective illness. Serotonin acts through specific cellular receptors that comprise at least 15 individual subtypes. These receptors can be grouped into at least four families based on structural and functional characteristics. The 5-HT1, 5-HT2 and 5-HT4 families are G-protein coupled receptors linked to enzymatic and electrical effector systems, while the 5-HT3 receptor is a gated ion channel.
The biosynthesis of 5-HT in the brain proceeds from the uptake of dietary tryptophan by the neuron, followed by its conversion to 5-hydroxytryptophan (abbreviated 5-HTP) by an enzyme called tryptophan hydroxlyase. 5-HTP is decarboxylated to 5-HT by an enzyme called L-aromatic amino acid decarboxylase (AADC). When administered to animals or humans, 5-HTP is rapidly decarboxylated by an enzyme called L-amino acid decarboxylase also commonly called peripheral decarboxylase. Carbidopa is an inhibitor of L-aromatic amino acid decarboxylase. Carbidopa does not enter the brain, and thus administration of carbidopa selectively blocks the conversion of 5-HTP to 5-HT in the periphery, but not the brain.
It has now been discovered that administration of various serotonin agonists and antagonists is effective in increasing milk production as well as a method of correcting certain mammalian lactation abnormalities.
Accordingly, in a preferred embodiment, the present invention is directed to the administration of active agents capable of inhibiting peripheral aromatic amino acid decarboxylase (AADC) enzymes, peripheral tryptophan hydroxylase (TPH) enzymes, peripheral serotonin (5-HT) enzymes, or a combination thereof for increasing milk production as well as for correcting certain mammalian lactation abnormalities.